The overall goal of this proposal is to gain insight into the process of carcinogenesis so that more effective anti- cancer therapies can be designed. As a first step, genes that regulate cancer must be identified. Secondly, it will be important to determine how the products of these genes normally function, and how these products are altered during tumorigenesis. Recent progress has identified CHD5 as a tumor suppressor gene mapping to human 1p36, a region of the genome that has been suspected to harbor such a cancer-preventing gene for three decades. Models with gain and loss of regions representing 1p36 were key in determining where the tumor suppressor resided. Further work identified CHD5 as the tumor suppressor in the region, and revealed that it acts as a master switch for a network of cancer-protective proteins. Indeed, CHD5 is frequently deleted in glioma, a type of brain cancer in humans. CHD5 is a protein with predicted chromatin-remodeling capabilities, suggesting that it has the power to regulate our genomes above and beyond the level of the DNA itself, potentially implicating CHD5 deficiency as the culprit in a variety of human malignancies. This proposal is focused on determining the impact of compromised CHD5 in human cancer and elucidating CHD5's mechanism of tumor suppression. This will be done by: 1) generating mouse models with altered CHD5 activity and monitoring cancer in these models. These models will also be used to investigate how errors in CHD5 or its associated tumor suppressive network which are found in human cancers thwart its tumor protective capabilities; 2) identifying human cancers that have defective CHD5; 3) elucidating the mechanistic basis of CHD5's ability to prevent cancer and determining how the inability of CHD5 to regulate the tumor suppressive network initiates tumorigenesis. Ultimately, figuring out how CHD5 normally works and defining the events that render it defective will lead to better treatments for a variety of human malignancies. Relevance: Deletion of the region of the genome encompassing CHD5 has been found in many human cancers including those affecting the brain and blood, as well as those occurring in common cancers such breast, colon, and prostate. Now that CHD5 has been shown to be a tumor suppressor in this region, its loss or inactivation could be responsible for many of these cancers. Therefore, a further study of the role of CHD5 in cancer is warranted to determine whether CHD5 offers novel strategies for designing more powerful anti-cancer therapies.